This invention relates to triamide-substituted heterobicyclic compounds. These compounds are inhibitors of microsomal triglyceride transfer protein (MTP) and/or apolipoprotein B (Apo B) secretion and are useful for the treatment of obesity and related diseases. These compounds are also useful for the prevention and treatment of atherosclerosis and its clinical sequelae, for lowering serum lipids, and in the prevention and treatment of related diseases. The invention further relates to pharmaceutical compositions comprising these compounds and to methods of treating obesity, atherosclerosis, and related diseases and/or conditions with said compounds, either alone or in combination with other medicaments, including lipid lowering agents. Further still, the invention relates to certain processes and intermediates related thereto which are useful in the preparation of the compounds of the instant invention.
Microsomal triglyceride transfer protein catalyzes the transport of triglyceride, cholesteryl ester, and phospholipids and has been implicated as a putative mediator in the assembly of Apo B-containing lipoproteins, biomolecules which contribute to the formation of atherosclerotic lesions. Specifically, the subcellular (lumen of the microsomal fraction) and tissue distribution (liver and intestine) of MTP have led to speculation that it plays a role in the assembly of plasma lipoproteins, as these are the sites of plasma lipoprotein assembly. The ability of MTP to catalyze the transport of triglyceride between membranes is consistent with this speculation, and suggests that MTP may catalyze the transport of triglyceride from its site of synthesis in the endoplasmic reticulum membrane to nascent lipoprotein particles within the lumen of the endoplasmic reticulum.
Accordingly, compounds which inhibit MTP and/or otherwise inhibit Apo B secretion are useful in the treatment of atherosclerosis and other conditions related thereto. Such compounds are also useful in the treatment of other diseases or conditions in which, by inhibiting MTP and/or Apo B secretion, serum cholesterol and triglyceride levels may be reduced. Such conditions may include, for example, hypercholesterolemia, hypertriglyceridemia, pancreatitis, and obesity; and hypercholesterolemia, hypertriglyceridemia, and hyperlipidemia associated with pancreatitis, obesity, and diabetes. For a detailed discussion, see for example, Wetterau et al., Science, 258, 999-1001, (1992), Wetterau et al., Biochem. Biophys. Acta., 875, 610-617 (1986), European patent application publication Nos. 0 584 446 A2, and 0 643 057 A1, the latter of which refers to certain compounds which have utility as inhibitors of MTP. Other examples of MTP inhibitors may be found in e.g., U.S. Pat. Nos. 5,712,279, 5,741,804, 5,968,950, 6,066,653, and 6,121,283; PCT International Patent Application publications WO 96/40640, WO 97/43257, WO 98/27979, WO 99/33800 and WO 00/05201; and European patent application publications EP 584446 and EP 643,057.
The present invention relates to compounds of the formula 1: 
or a pharmaceutically acceptable salt thereof, wherein:
R1 is substituted at the 5 or 6 position of formula 1 and has the structure: 
m is an integer from 0 to 5;
n is an integer from 0 to 3;
p is an integer from 0 to 3;
L is xe2x80x94C(O)N(R9)xe2x80x94, i.e., L has the structure: 
X is N or C(Rc);
R2, R8, R11, R12, R13 and R16 are each independently selected from halo, cyano, nitro, azido, amino, hydroxy, (C1-C6)alkyl, (C2-C6)alkoxy, methoxy, (C1-C6)alkoxy(C1-C6)alkyl, mono-, di- or tri-halo(C2-C6)alkyl, perfluoro(C2-C4)alkyl, trifluoromethyl, trifluoromethyl(C1-C5)alkyl, mono-, di- or tri-halo(C2-C6)alkoxy, trifluoromethyl(C1-C5)alkoxy, (C1-C6)alkylthio, hydroxy(C1-C6)alkyl, (C3-C8)cycloalkyl(CRaRb)qxe2x80x94, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylamino-, (C1-C6)dialkylamino, amino(C1-C6)alkyl-, xe2x80x94(CRaRb)qNRaR14, xe2x80x94C(O)NRaR14, xe2x80x94NR14 C(O)R15, xe2x80x94NR14OR15, xe2x80x94CHxe2x95x90NOR15, xe2x80x94NR14C(O)OR15, xe2x80x94NR14S(O)jR15, xe2x80x94C(O)R15, xe2x80x94C(O)OR15, xe2x80x94OC(O)R15, xe2x80x94SO2NRaR14, xe2x80x94S(O)jR15, or xe2x80x94(CRaRb)qS(O)jR15;
each Ra and Rb is independently H or (C1-C6)alkyl;
Rc is H or R11;
each q is independently an integer from 0 to 6;
each j is independently 0, 1 or 2;
R3 is H, halo, (C1-C6)alkyl, or mono-, di- or tri-halo(C1-C6)alkyl;
R4 is H, (C1-C6)alkyl, (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)tO(C1-C6 alkyl), xe2x80x94(CRaRb)tS(C1-C6alkyl), xe2x80x94(CRaRb)rC(O)R15, xe2x80x94(CRaRb)rR15, xe2x80x94SO2R15 or xe2x80x94(CRaRb)q-phenyl, wherein the phenyl moiety is optionally substituted with from one to five independently selected R16;
each r is independently an integer from 2 to 5;
each t is independently an integer from 1 to 6;
R5, R6 and R9 are each independently H, (C1-C6)alkyl, (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)tO(C1-C6alkyl), xe2x80x94(CRaRb)tS(C1-C6alkyl), xe2x80x94(CRaRb)rR15 or xe2x80x94SO2R15;
R7 is phenyl, pyridyl, phenyl-Z1xe2x80x94 or pyridyl-Z1xe2x80x94, wherein the phenyl or pyridyl moiety is optionally substituted with one to five independently selected R12;
Z1 is xe2x80x94SO2xe2x80x94 or xe2x80x94(CRaRb)vxe2x80x94;
v is independently an integer from 1 to 6;
R10 is phenyl, pyridyl, phenyl-Z2xe2x80x94 or pyridyl-Z2xe2x80x94, wherein the phenyl or pyridyl moiety is optionally substituted with one to five independently selected R13;
Z2 is xe2x80x94S(O)jxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94(CRaRb)wxe2x80x94, or xe2x80x94(O)k(CRaRb)w(O)k(CRaRb)qxe2x80x94;
w is independently an integer from 1 to 6;
each k is independently 0 or 1;
each R14 is independently H, (C1-C6)alkyl, (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)tO(C1-C6alkyl), xe2x80x94(CRaRb)tS(C1-C6alkyl), xe2x80x94(CRaRb)rC(O)R15, xe2x80x94(CRaRb)tR15 or xe2x80x94SO2R15;
each R15 is independently H, (C1-C6)alkyl, (C3-C8)cycloalkyl, trifluoromethyl, trifluoromethyl(C1-C5)alkyl, wherein the alkyl, moieties of the foregoing R15 groups are independently optionally substituted with 1 to 3 substituents independently selected from C1-C6alkyl, C1-C6alkoxy, amino, hydroxy, halo, cyano, nitro, trifluoromethyl and trifluoromethoxy;
and wherein any of the above xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d or xe2x80x9calkynylxe2x80x9d moieties comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not substituted with halogen, SO or SO2, or attached to a N, O or S atom, optionally bears on said methyl, methylene or methine group a substituent selected from the group consisting of halo, xe2x80x94ORa, xe2x80x94SRa and xe2x80x94NRaRb.
In an embodiment of the invention, L is attached to the 2 position of R1 and to the 5 position of formula 1, i.e., the compound of formula 1 has the structure of formula 1a: 
In another embodiment of the invention, L is attached to the 2 position of R1 and to the 5 position of formula 1, and R10 is attached at the 3xe2x80x2 position.
In another embodiment of the invention, L is attached to the 3 position of R1 and to the 5 position formula 1. In another embodiment of the invention, L is attached to the 3 position of R1 and to the 5 position of formula 1 and X is N. In still another embodiment of the invention, L is attached to the 3 position of R1 and to the 5 position of formula 1, X is N and R10 is attached at the 2 position of R1. In other embodiments of the invention, the attachment of L to R1 is selected from the 3, 4, 6 or 6 position and the attachment of L to the compound of formula 1 is selected from the 5 position or 6 position.
In another embodiment of the invention, X is C(Rc).
In another embodiment of the invention, X is C(Rc), m is 0, n is 0, and p is 0 or 1.
In another embodiment of the invention, X is C(Rc), m is 0, n is 0, and p is 0 or 1, and R10 is phenyl-Z2xe2x80x94 attached at the 3 position of R1, wherein the phenyl moiety of R10 is optionally substituted with one to five independently selected R13.
In another embodiment of the invention, X is C(Rc), m is 0, n is 0, and p is 0 or 1, and R10 is phenyl attached at the 3 position of R1, wherein the phenyl moiety of R10 is optionally substituted with one to five independently selected R13.
In another embodiment of the invention, R7 is phenyl-Z1, wherein the phenyl moiety is optionally substituted with one to five independently selected R12. In a preferred embodiment of the invention, Z1 is xe2x80x94(CRaRb)vxe2x80x94, and in a more preferred embodiment, Z1 is methylene, i.e., xe2x80x94CH2xe2x80x94.
In another embodiment of the invention, R4, R5, R6 and R9 are each independently selected from H, (C1-C6)alkyl, xe2x80x94(CRaRb)qO(C1-C6alkyl) or xe2x80x94(CRaRb)rR15.
In another embodiment of the invention, each R12 is independently selected from halo, hydroxy, (C1-C6)alkyl, methoxy, (C2-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, mono-, di- or tri-halo(C2-C6)alkyl, trifluoromethyl, trifluoromethyl(C1-C5)alkyl, mono-, di- or tri-halo(C2-C6)alkoxy, trifluoromethyl(C1-C6)alkoxy, (C1-C6)alkylthio and hydroxy(C1-C6)alkyl.
In another embodiment of the invention, each R13 is independently selected from halo, hydroxy, amino, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, methoxy, (C2-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, mono-, di- or tri-halo(C2-C6)alkyl, trifluoromethyl, trifluoromethyl(C1-C5)alkyl, mono-, di- or tri-halo(C2-C6)alkoxy, trifluoromethyl(C1-C5)alkoxy, (C1-C6)alkylthio, hydroxy(C1-C6)alkyl, xe2x80x94C(O)OR15 and xe2x80x94NR14C(O)R15; wherein R14 is H or (C1-C6)alkyl; and wherein R15 is H or (C1-C6)alkyl.
In another embodiment of the invention, R10 is phenyl attached at the 3 position of R1, wherein the phenyl moiety of R10 is optionally substituted with one R13. In a preferred embodiment, R10 and R1 both are phenyl, such that R1 and R10 together form a 1,1xe2x80x2-biphenyl group, wherein R10 comprises the 1xe2x80x2-6xe2x80x2 positions of the biphenyl group and R13 is substituted at the 4xe2x80x2 position of the biphenyl.
In another embodiment of the invention, R4 is H, (C1-C6)alkyl or xe2x80x94(CRaRb)qO(C1-C6alkyl).
In another embodiment of the invention, the carbon designated xe2x80x9caxe2x80x9d in formula 1 is in the xe2x80x9c(S)xe2x80x9d configuration.
In a preferred embodiment of the invention, R13 is trifluoromethyl.
In another preferred embodiment of the invention, R3 is H, halo, or (C1-C6)alkyl.
In a more preferred embodiment of the invention, R6 is methyl.
In a particularly preferred embodiment of the invention, the compound of formula 1 is (S)-1-ethyl-5-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}amide.
In another particularly preferred embodiment of the invention, the compound of formula 1 is (S)xe2x80x94N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4xe2x80x2-(trifluoromethyl)[1,1xe2x80x2-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide.
In another more preferred embodiment of the invention R3 is chloro.
In another particularly preferred embodiment of the invention, the compound of formula 1 is selected from the group consisting of:
3-chloro-5-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}amide;
3-chloro-1-methyl-5-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}amide;
4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid [2-({[(benzyl-methyl-carbamoyl)-phenyl-methyl]-methyl-amino}-methyl)-3-chloro-1-methyl-1H-indol-5-yl]-amide, which is alternately named: 3-chloro-1-methyl-5-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid {N-[2-(benzyl(methyl)amino)-2-oxo-1-phenylethyl]methyl}amide;
3-chloro-1-methyl-5-[methyl-(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}amide; and
3-chloro-1-ethyl-5-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}amide.
In another embodiment of the invention, X is C(Rc), m is 0, n is 0, and p is 0 or 1, and R10 is phenyl-Z2xe2x80x94attached at the 3xe2x80x2-position, wherein the phenyl moiety of R10 is optionally substituted with one to five independently selected R13 and Z2 is O or S.
In another embodiment of the invention, R7 is phenyl-Z1, wherein the phenyl moiety is optionally substituted with one to five independently selected R12 and Z1 is O or S.
In another embodiment of the invention, R7 is pyridyl-Z1, wherein the pyridyl moiety is optionally substituted with from one to five independently selected R12. In a preferred embodiment thereof, Z1 is xe2x80x94(CH2)xe2x80x94.
In another embodiment of the invention, X is N and R10 is phenyl optionally substituted with one to five independently selected R13.
In another embodiment of the invention, X is N and R10 is phenyl optionally substituted with one to five independently selected R13, and R7 is phenyl-Z1, wherein the phenyl moiety is optionally substituted with from one to five independently selected R12.
The present invention also relates to a compound of the formula 1b: 
or a pharmaceutically acceptable salt thereof, wherein:
R1 is substituted at the 5 or 6 position of formula 1b and has the structure: 
or when R7 is phenyl, pyridyl, phenyl-Z1xe2x80x94 or pyridyl-Z1xe2x80x94 optionally substituted with one to five independently selected R12, R1 is (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5-C10)bicycloalkyl, xe2x80x94(CRaRb)tO(C1-C6alkyl), xe2x80x94(CRaRb)tS(C1-C6alkyl), xe2x80x94(CRaRb)rC(O)R15, xe2x80x94(CRaRb)rR15, xe2x80x94SO2R15(C4-C10)heterocyclyl, (C5-C10)heteroaryl, aryl or xe2x80x94(CRaRb)q-aryl, wherein the cycloalkyl, heterocyclyl, heteroaryl or aryl moiety is optionally substituted with from one to five independently selected R16;
m is an integer from 0 to 5;
n is an integer from 0 to 3;
p is an integer from 0 to 3;
L is xe2x80x94C(O)N(R9)xe2x80x94, as described above;
X1 is N(R4), S or O;
X2 is N or C(Rc);
R2, R8, R11, R12, R13 and R16 are each independently selected from halo, cyano, nitro, azido, amino, hydroxy, (C1-C6)alkyl, (C2-C6)alkoxy, methoxy, (C1-C6)alkoxy(C1-C6)alkyl, mono-, di- or tri-halo(C2-C6)alkyl, perfluoro(C2-C4)alkyl, trifluoromethyl, trifluoromethyl(C1-C5)alkyl, mono-, di- or tri-halo(C2-C6)alkoxy, trifluoromethyl(C1-C5)alkoxy, (C1-C6)alkylthio, hydroxy(C1-C6)alkyl, (C3-C8)cycloalkyl(CRaR0)qxe2x80x94, (C2-C6)alkenyl, (C2-C6)alkynyl, (C2-C6)alkylamino-, (C1-C6)dialkylamino, amino(C1-C6)alkyl-, xe2x80x94(CRaRb)qNRaR14, xe2x80x94C(O)NRaR14, xe2x80x94NR14C(O)R15, xe2x80x94NR14OR15, xe2x80x94CHxe2x95x90NOR15, xe2x80x94NR14C(O)OR15, xe2x80x94NR14S(O)jR15, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94C(O)OR15, xe2x80x94OC(O)R15, xe2x80x94SO2NRaR14, xe2x80x94S(O)jR15 or xe2x80x94(CRaRb)qS(O)jR15;
each Ra and Rb is independently H or (C1-C6)alkyl;
Rc is H or R11;
each q is independently an integer from 0 to 6;
each j is independently 0, 1 or 2;
R3 is H, halo, (C1-C6)alkyl, or mono-, di- or tri-halo(C1-C6)alkyl;
R4 is H, (C1-C6)alkyl, (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)tO(C1-C6alkyl), xe2x80x94(CRaRb)tS(C1-C6alkyl), xe2x80x94(CRaRb)rC(O)R15, xe2x80x94(CRaRb)rR15, xe2x80x94SO2R15 or xe2x80x94(CRaRb)qxe2x80x94phenyl, wherein the phenyl moiety is optionally substituted with from one to five independently selected R16;
each r is independently an integer from 2 to 5;
each t is independently an integer from 1 to 6;
R5 and R9 are each independently H, (C1-C6)alkyl, (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)tO(C1-C6alkyl), xe2x80x94(CRaRb)tS(C1-C6alkyl), xe2x80x94(CRaRb)rC(O)R15, xe2x80x94(CRaRb)rR15 or xe2x80x94SO2R15;
R6 is H, (C1-C6)alkyl, (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)qO(C1-C6alkyl), xe2x80x94(CRaRb)qS(C1-C6alkyl), xe2x80x94(CRaRb)rC(O)R15, xe2x80x94(CRaRb)rR15 or xe2x80x94SO2R15;
y is an integer from 0 to 5;
R7 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, xe2x80x94(CRaRb)qO(C1-C6alkyl), xe2x80x94(CRaRb)qS(C1-C6alkyl); (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)rC(O)R15, xe2x80x94(CRaRb)rC(S)R15, xe2x80x94(CRaRb)rR15 or xe2x80x94SO2R15;
or R7 is phenyl, pyridyl, phenyl-Z1xe2x80x94 or pyridyl-Z1xe2x80x94 optionally substituted with one to five independently selected R12;
or R6 and R7 taken together with the nitrogen atom to which they are attached together comprise (C4-C10)heterocyclyl, wherein the heterocyclyl moiety is monocyclic;
wherein the alkyl, cycloalkyl, and heterocyclyl moieties of the foregoing R6 and R7 groups are optionally substituted independently with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR15, xe2x80x94C(O)R15, xe2x80x94C(O)OR15, xe2x80x94OC(O)R15, xe2x80x94NR14C(O)R15, xe2x80x94C(O)NRaR14, xe2x80x94NRaR14, and xe2x80x94NR14OR15,C1-C6alkyl, C2-C6 alkenyl, and C2-C6 alkynyl; and
R10 is phenyl, pyridyl, phenyl-Z2xe2x80x94 or pyridyl-Z2xe2x80x94, wherein the phenyl or pyridyl moiety is optionally substituted with one to five independently selected R13;
Z2 is xe2x80x94S(O)jxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94(CRaRb)wxe2x80x94, or xe2x80x94(O)k(CRaRb)w(O)k(CRaRb)qxe2x80x94;
w is independently an integer from 1 to 6;
each k is independently 0 or 1;
or R10 is OR17, wherein R17 is (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, mono-, or tri-halo (C2-C6)alkyl, perfluoro(C2-C4)alkyl, trifluoromethyl(C1-C5)alkyl, hydroxy(C1-C6)alkyl, (C3-C8)cycloalkyl(CRaRb)qxe2x80x94, (C2-C6)alkenyl, or (C2-C6)alkynyl;
each R14 is independently H, (C1-C8)alkyl, (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)tO(C1-C6alkyl), xe2x80x94(CRaRb)tS(C1-C6alkyl), xe2x80x94(CRaRb)rC(O)R15, xe2x80x94(CRaRb)tR15 or xe2x80x94SO2R15;
each R15 is independently H, (C1-C6)alkyl, (C3-C8)cycloalkyl, trifluoromethyl, trifluoromethyl(C1-C5)alkyl, wherein the alkyl, moieties of the foregoing R15 groups are independently optionally substituted with 1 to 3 substituents independently selected from C1-C6alkyl, C1-C6alkoxy, amino, hydroxy, halo, cyano, nitro, trifluoromethyl and trifluoromethoxy;
and wherein any of the above xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d or xe2x80x9calkynylxe2x80x9d moieties comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not substituted with halogen, SO or SO2, or attached to a N, O or S atom, optionally bears on said methyl, methylene or methine group a substituent selected from the group consisting of halo, xe2x80x94ORa, xe2x80x94SR8 and xe2x80x94NRaRb.
In an embodiment of the invention, X2 is C(Rc).
In another embodiment of the invention, X2 is C(Rc) and L is attached to the 2 position of R1 and to the 5 position of formula 1b.
In another embodiment of the invention, X2 is C(Rc) and L is attached to the 2 position of R1 and to the 5 position of formula 1b, R10 is OR17 and R7 is phenyl-Z1, wherein the phenyl moiety is optionally substituted with one to five independently selected R12. In a preferred embodiment thereof, Z1 is xe2x80x94(CRaRb)txe2x80x94.
In another embodiment of the invention, X2 is C(Rc) and L is attached to the 2 position of R1 and to the 5 position of formula 1b, and R10 is phenyl attached at the 3 position of R1, wherein the phenyl moiety of R10 is optionally substituted with one to five independently selected R13. In a preferred embodiment of the invention, R6 in formula 1b is H or (C1-C4)alkyl.
In another preferred embodiment of the invention, the carbon designated xe2x80x9caxe2x80x9d in formula 1b is in the (S) absolute configuration.
In another embodiment of the invention, R13 in formula 1b is H or trifluoromethyl.
In another preferred embodiment of the invention, R13 in formula 1b is H, halo, or (C1-C6)alkyl
In another preferred embodiment of the invention, R7 in formula 1b is (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl.
In a particularly preferred embodiment of the invention, the compound is selected from the group consisting of:
3-Chloro-1-methyl-5-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid [2-oxo-1-phenyl-2-(prop-2-ynylamino)ethyl]amide;
3-Chloro-1-methyl-5-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid [2-(isopropylamino-2-oxo-1-phenylethyl]amide;
3-Chloro-1-methyl-5-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid [2-oxo-1-phenyl-2-(propylamino)ethyl]amide;
3-Chloro-1-methyl-5-[methyl-(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid [2-(ethylamino)-2-oxo-1-phenylethyl]amide;
3-Chloro-1-methyl-5-[methyl-(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid [2-(isopropylamino-2-oxo-1-phenylethyl]amide;
5-[(Biphenyl-2-carbonyl)-amino]-3-chloro-1-methyl-1H-indole-2-carboxylic acid [2-oxo-1-phenyl-2-(propylamino)ethyl]amide; and
5-[(Biphenyl-2-carbonyl)-amino]-3-chloro-1-methyl-1H-indole-2-carboxylic acid [2-(isopropylamino-2-oxo-1-phenylethyl]amide.
In an embodiment of the invention, R6 and R7 in formula 1b taken together with the nitrogen atom to which they are attached together comprise (C4-C10)heterocyclyl, wherein the heterocyclyl is optionally substituted independently with 1 or 2 substituents independently selected from (C1-C8)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl and trifluoromethyl. In a preferred embodiment thereof, the heterocyclyl is selected from pyrrolidinyl, piperidinyl, morpholino and thiomorpholino. In a particularly preferred embodiment thereof, the heterocyclyl is pyrrolidinyl or morpholino.
The present invention also relates to compounds of the formula 2: 
or a pharmaceutically acceptable salt thereof, wherein:
R1 is substituted at the 5 or 6 position of formula 1 and has the structure: 
m is an integer from 0 to 5;
n is an integer from 0 to 3;
p is an integer from 0 to 3;
L is xe2x80x94C(O)N(R9)xe2x80x94;
X is N or C(Rc);
R2, R8, R11, R12 and R13 are each independently selected from halo, cyano, nitro, azido, amino, hydroxy, (C1-C6)alkyl, (C2-C6)alkoxy, methoxy, (C1-C6)alkoxy(C1-C6)alkyl, mono-, di- or tri-halo(C2-C6)alkyl, perfluoro(C2-C4)alkyl, trifluoromethyl, trifluoromethyl(C1-C5)alkyl, mono-, di- or tri-halo(C2-C6)alkoxy, trifluoromethyl(C1-C5)alkoxy, (C1-C6)alkylthio, hydroxy(C1-C6)alkyl, (C3-C8)cycloalkyl(CRaRb)qxe2x80x94, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylamino-, (C1-C6)dialkylamino, amino(C1-C6)alkyl-, xe2x80x94(CRaRb)qNRaR14, xe2x80x94C(O)NRaR14, xe2x80x94NR14C(O)R15, xe2x80x94NR14OR15, xe2x80x94CHxe2x95x90NOR15, xe2x80x94NR14C(O)OR15, xe2x80x94NR14S(O)R15, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94C(O)OR15,xe2x80x94OC(O)R15, xe2x80x94SO2NRaR14, xe2x80x94S(O)jR15, or xe2x80x94(CRaRb)qS(O)jR15;
each Ra and Rb is independently H or (C1-C6)alkyl;
Rc is H or R11;
each q is independently an integer from 0 to 6;
each j is independently 0, 1 or 2;
R3 is H, halo, (C1-C6)alkyl, or mono-, di- or tri-halo(C1-C6)alkyl;
each r is independently an integer from 2 to 5;
each t is independently an integer from 1 to 6;
R5 and R9 are each independently H, (C1-C6)alkyl, (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)tO(C1-C6alkyl), xe2x80x94(CRaRb)tS(C1-C6alkyl), xe2x80x94(CRaRb)rC(O)R15, xe2x80x94(CRaRb)rR15 or xe2x80x94SO2R15;
R6 is H, (C1-C6)alkyl, (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)qO(C1-C6alkyl), xe2x80x94(CRaRb)qS(C1-C6alkyl), xe2x80x94(CRaRb)rC(O)R15, xe2x80x94(CRaRb)rR15 or xe2x80x94SO2R15;
y is an integer from 0 to 5;
R7 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, xe2x80x94(CRaRb)qO(C1-C6alkyl), xe2x80x94(CRaRb)qS(C1-C6alkyl); (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)rC(O)R15, xe2x80x94(CRaRb)rC(S)R15, xe2x80x94(CRaRb)rR15 or xe2x80x94SO2R15;
or R7 is phenyl, pyridyl, phenyl-Z1xe2x80x94 or pyridyl-Z1xe2x80x94 optionally substituted with one to five independently selected R12;
or R6 and R7 taken together with the nitrogen atom to which they are attached together comprise (C4-C10)heterocyclyl, wherein the heterocyclyl moiety is monocyclic;
wherein the alkyl, cycloalkyl, and heterocyclyl moieties of the foregoing R6 and R7 groups are optionally substituted independently with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR15, xe2x80x94C(O)R15, xe2x80x94C(O)OR15, xe2x80x94OC(O)R15, xe2x80x94NR14C(O)R15, xe2x80x94C(O)NRaR14, xe2x80x94NRaR14, and xe2x80x94NR14OR15, C1-C6alkyl, C2-C6 alkenyl, and C2-C6 alkynyl; and
R10 is phenyl, pyridyl, phenyl-Z2xe2x80x94 or pyridyl-Z2xe2x80x94, wherein the phenyl or pyridyl moiety is optionally substituted with one to five independently selected R13;
Z2 is xe2x80x94S(O)jxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94(CRaRb)wxe2x80x94, or xe2x80x94(O)k(CRaRb)w(O)k(CRaRb)qxe2x80x94;
w is independently an integer from 1 to 6;
each k is independently 0 or 1;
or R10 is OR17, wherein R17 is (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, mono-, di- or tri-halo(C2-C6)alkyl, perfluoro(C2-C4)alkyl, trifluoromethyl(C1-C5)alkyl, hydroxy(C1-C6)alkyl, (C3-C8)cycloalkyl(CRaRb)qxe2x80x94, (C2-C6)alkenyl, or (C2-C6)alkynyl;
each R14 is independently H, (C1-C6)alkyl, (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)tO(C1-C6alkyl), xe2x80x94(CRaRb)tS(C1-C6alkyl), xe2x80x94(CRaRb)rC(O)R15 or xe2x80x94SO2R15;
each R15 is independently H, (C1-C6)alkyl, (C3-C8)cycloalkyl, trifluoromethyl, trifluoromethyl(C1-C5)alkyl, wherein the alkyl, moieties of the foregoing R15 groups are independently optionally substituted with 1 to 3 substituents independently selected from C1-C6alkyl, C1-C6alkoxy, amino, hydroxy, halo, cyano, nitro, trifluoromethyl and trifluoromethoxy;
and wherein any of the above xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d or xe2x80x9calkynylxe2x80x9d moieties comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not substituted with halogen, SO or SO2, or attached to a N, O or S atom, optionally bears on said methyl, methylene or methine group a substituent selected from the group consisting of halo, xe2x80x94ORa, xe2x80x94SRa and xe2x80x94NRaRb.
In an embodiment of the invention, X in formula 2 is C(Rc).
In another embodiment of the invention, L in formula 2 is attached to the 2 position of R1 and to the 5 position of formula 2.
In another embodiment of the invention, wherein y is 1 or 2.
In another embodiment of the invention, R10 in formula 2 is phenyl attached at the 3 position of R1, wherein the phenyl moiety of R10 is optionally substituted with one to five independently selected R13.
In another embodiment of the invention, R7 in formula 2 is phenyl-Z1, wherein the phenyl moiety is optionally substituted with one to five independently selected R12. In a preferred embodiment thereof, Z1 is xe2x80x94(CRaRb)txe2x80x94.
In another embodiment of the invention, R6 in formula 2 is H or (C1-C4)alkyl.
In another embodiment of the invention, the carbon designated xe2x80x9caxe2x80x9d in formula 2 is in the (S) absolute configuration.
In a preferred embodiment of the invention, R13 in formula 2 is trifluoromethyl.
In another preferred embodiment of the invention, R3 in formula 2 is H, halo, or (C1-C6)alkyl.
The invention also relates to a process for preparing a compound of formula 1 which comprises forming an amide linkage between a compound of the formula AB1: 
and a compound of the formula C: 
wherein
m is an integer from 0 to 5; n is an integer from 0 to 3; p is an integer from 0 to 3;
the amido nitrogen atom of xe2x80x94C(O)N(R9)xe2x80x94 above is bonded to the 5 or 6 position of the indole;
X is N or C(Rc), wherein Rc is H or R11;
R2, R8, R11, R12, R13 and R16 are each independently selected from halo, cyano, nitro, azido, amino, hydroxy, (C1-C6)alkyl, (C2-C6)alkoxy, methoxy, (C1-C6)alkoxy(C1-C6)alkyl, mono-, di- or tri-halo(C2-C6)alkyl, perfluoro(C2-C4)alkyl, trifluoromethyl, trifluoromethyl(C1-C5)alkyl, mono-, di- or tri-halo(C2-C6)alkoxy, trifluoromethyl(C1-C5)alkoxy, (C1-C6)alkylthio, hydroxy(C1-C6)alkyl, (C3-C8)cycloalkyl(CRaRb)qxe2x80x94, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylamino-, (C1-C6)dialkylamino, amino(C1-C6)alkyl-, xe2x80x94(CRaRb)qNRaR14, xe2x80x94C(O)NRaR14, xe2x80x94NR14C(O)R15, xe2x80x94NR14OR15, xe2x80x94CHxe2x95x90NOR15, xe2x80x94NR14C(O)OR15, xe2x80x94NR14S(O)jR15, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94C(O)OR15, xe2x80x94OC(O)R15, xe2x80x94SO2NRaR14, xe2x80x94S(O)jR15, or xe2x80x94(CRaRb)qS(O)jR15;
each Ra and Rb is independently H or (C1-C6)alkyl;
each q is independently an integer from 0 to 6; each j is independently 0, 1 or 2;
R3 is H, halo, (C1-C6)alkyl, or mono-, di- or tri-halo(C1-C6)alkyl;
R4 is H, (C1-C6)alkyl, (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb),tO(C1-C6alkyl), xe2x80x94(CRaRb)tS(C1-C6alkyl), xe2x80x94(CRaRb)rC(O)R15, xe2x80x94(CRaRb)rR15, xe2x80x94SO2R15 or xe2x80x94(CRaRb)q-phenyl, wherein the phenyl moiety is optionally substituted with from one to five independently selected R16;
each r is independently an integer from 2 to 5; each t is independently an integer from 1 to 6;
R5, R6 and R9 are each independently H, (C1-C8)alkyl, (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)tO(C1-C6alkyl), xe2x80x94(CRaRb)tS(C1-C6alkyl), xe2x80x94(CRaRb)rC(O)R15, xe2x80x94)CRaRb)rR15 or xe2x80x94SO2R15;
R7 is phenyl, pyridyl, phenyl-Z1xe2x80x94 or pyridyl-Z1xe2x80x94, wherein the phenyl or pyridyl moiety is optionally substituted with one to five independently selected R12;
Z1 is xe2x80x94SO2xe2x80x94 or xe2x80x94(CRaRb)vxe2x80x94;
v is independently an integer from 1 to 6;
R10 is phenyl, pyridyl, phenyl-Z2xe2x80x94 or pyridyl-Z2xe2x80x94, wherein the phenyl or pyridyl moiety is optionally substituted with one to five independently selected R13;
Z2 is xe2x80x94S(O)jxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94(CRaRb)wxe2x80x94, or xe2x80x94(O)k(CRaRb)w, (O)k(CRaRb)qxe2x80x94;
w is independently an integer from 1 to 6;
each k is independently 0 or 1;
each R14 is independently H, (C1-C6)alkyl, (C3-C8)cycloalkyl, xe2x80x94C(O)R15, xe2x80x94C(S)R15, xe2x80x94(CRaRb)tO(C1-C6alkyl), xe2x80x94(CRaRb)tS(C1-C6alkyl), xe2x80x94(CRaRb)rC(O)R15, xe2x80x94(CRaRb)tR15 or xe2x80x94SO2R15;
each R15 is independently H, (C1-C6)alkyl, (C3-C8)cycloalkyl, trifluoromethyl, trifluoromethyl(C1-C5)alkyl, wherein the alkyl, moieties of the foregoing R15 groups are independently optionally substituted with 1 to 3 substituents independently selected from C1-C6alkyl, C1-C6alkoxy, amino, hydroxy, halo, cyano, nitro, trifluoromethyl and trifluoromethoxy;
and wherein any of the above xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d or xe2x80x9calkynylxe2x80x9d moieties comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not substituted with halogen, SO or SO2, or attached to a N, O or S atom, optionally bears on said methyl, methylene or methine group a substituent selected from the group consisting of halo, xe2x80x94ORa, xe2x80x94SRa and xe2x80x94NRaRb;
and Lc is selected from a (i) a carboxylic acid or salt thereof (ii) an activated form of the carboxylic acid or (iii) an aldehyde.
In an embodiment, the carboxylic acid is optionally activated in-situ, using methods well known in the art. The above process is referred to herein as xe2x80x9cProcess I.xe2x80x9d Process I is applicable to, and provides, a process for preparing each of the embodiments, preferred embodiments, more preferred embodiments and particularly preferred embodiments of the compound of formula 1, a detailed repetition of which is avoided for brevity. Methods for forming amide linkages are well-known in the art, some examples of which are provided herein.
In an embodiment, the employed form of the amine C may optionally be a salt with any acid that is compatible with the subsequent process options, and may additionally or optionally be a solution in a similarly compatible solvent or mixture of solvents.
In an embodiment, the employed forms of the carboxylic acid (or salt thereof) AB1 and amine C (or salt thereof) optionally include solvates and hydrates.
In an embodiment of Process I, the amide linkage between AB1 and C is formed by combining AB1, C, and PyBroP (about 1 eq) in a suitable non-aqueous solvent, followed by the addition of diisopropylethylamine (2-3 eq). In a preferred embodiment, the suitable solvent is methylene chloride or DMF. In a more preferred embodiment of Process I, the solvent is methylene chloride. In another preferred embodiment, Process I further comprises stirring or agitating the resulting mixture at room temperature for a period of from about 30 minutes to about 24 hours. In another preferred embodiment thereof, of Process I further comprises removal of the solvent and the purification of the product by TLC or flash chromatography using ethyl acetate/hexane as the eluting solvent.
In another embodiment of Process I, the amide linkage between AB1, wherein Lc is an aldehyde, preferably C(O)H, and C is formed by a process (herein, the xe2x80x9cAldehyde Processxe2x80x9d) which comprises (a) reacting the AB1 aldehyde with C in the presence of an acid, preferably acetic acid, in a suitable solvent, preferably methylene chloride, followed by (b) addition of NaB(OAc)3H and chloroform. In an preferred embodiment of the Aldehyde Process, the compound of formula 1 is purified from the organic layer, preferably by flash chromatography using methanol/chloroform. In a further embodiment of the Aldehyde Process, the AB1 aldehyde is formed by (i) combining a compound of formula AB1, wherein Lc is a carboxylic acid, preferably xe2x80x94COOH, with N,O-dimethyl hydroxylamine hydrochloride salt and PyBroP in a suitable solvent; followed by (ii) addition of diisopropylethylamine and (iii) treatment of the resulting N,O-dimethyl hydroxyamide with DIBAL in a suitable solvent, to yield the corresponding aldehyde. In a preferred embodiment of the Aldehyde Process, the suitable solvent in step (i) is methylene chloride. In another preferred embodiment of the Aldehyde Process, the suitable solvent in step (iii) is THF.
In a preferred embodiment of Process I, referred to herein as xe2x80x9cProcess ICxe2x80x9d for its use of carbodiimide, the amide linkage between AB1 and C, wherein Lc is a carboxylic acid, is formed by (a) combining AB1 with a carbodiimide and a catalyst, e.g., 1-hydroxybenzotriazole hydrate (xe2x80x9cHOBtxe2x80x9d), in a suitable non-aqueous solvent, and (b) adding triethylamine and C to the mixture of step (a). In a more preferred embodiment of Process IC, the carbodiimide is EDC, i.e., 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride, and even more preferably, the solvent is methylene chloride. In another embodiment, Process IC further comprises at least a second addition of triethylamine. In another embodiment, Process IC further comprises at least a second addition of triethylamine, optionally with further addition of the carbodiimide. In another embodiment of Process IC, a salt of the acid AB1 is used in step (a). Preferably, the salt is a sodium salt, i.e., Lc is xe2x80x94C(O)Oxe2x88x92Na+, and more preferably, the salt is a potassium salt, i.e., Lc is xe2x80x94C(O)Oxe2x88x92K+, and particularly preferably, the salt is a potassium salt, i.e., Lc is xe2x80x94C(O)Oxe2x88x92K+, crystallizing as the 2.5 mole hydrate. In a still further embodiment thereof, the acid salt AB1 is first treated with aqueous acid before combination with the other components in step (a); in this embodiment, the treatment with aqueous acid resulting in precipitation of the free acid as a solid, which is collected for use in step (a). In a preferred embodiment of the acid treatment step, the acid salt AB1 is treated with aqueous acid adjusted to a pH of from about 3 to about 4, with heating. In a more preferred embodiment, the acid salt is treated with an inert mineral acid, most preferably concentrated aqueous hydrochloric acid, or alternatively, an inert organic acid, preferably anhydrous and most preferably methanesulfonic acid, before step (a). In a still further embodiment, the compound of formula 1 is purified by (a) washing in saturated aqueous sodium hydrogen carbonate, (b) washing in aqueous acid, preferably, hydrochloric acid, and (c) washing with water, to provide purified compound of formula 1 in the non-aqueous solvent. In a still further embodiment, the non-aqueous solvent is replaced with amyl acetate, amyl alcohol, mixtures of methanol or acetonitrile with diisopropyl ether, or preferably mixtures of propan-2-ol and teff-butyl methyl ether, by distillation, and the solution is cooled in order to precipitate solid forms, e.g., polymorphs, of the compound of formula 1. Preferably, the solution of compound of formula 1 in mixtures of propan-2-ol and tert-butyl methyl ether is seeded with the desired solid form to facilitate precipitation of the desired solid form.
In another embodiment of the above process, the amide linkage between AB1 and C is formed by (a) reaction of the acid the 1,1xe2x80x2-carbonyldiiimidazole to produce its acyl imidazolide, i.e., yielding e.g., Lcxe2x95x90xe2x80x94C(O)(1-C3H3N2), and (b) reacting the imidazolide of AB1 with C, preferably in the presence of a suitable base. In this embodiment, some racemization of chiral center xe2x80x9caxe2x80x9d in (S)-phenylglycine derivatives has been observed, thus, where preservation of stereochemistry is desirable, the use of the imidazolide reaction is less preferred than other embodiments described above. Preferred processes of the invention preserve the stereochemistry of the phenylglycine group.
In a preferred embodiment of each of the embodiments of Process I and Process IC, R5 is hydrogen, R6 is hydrogen, R7 is benzyl, m, n and p are all 0, and the carbon designated xe2x80x9caxe2x80x9d in formula C is in the (S) configuration. In another preferred embodiment of Process I, the amide linkage between AB1 and C is formed as in Example 45, step (g). In a preferred embodiment of Process IC, R4 is methyl, R5 is hydrogen, R6 is methyl, R7 is benzyl, m is 0 and the carbon designated xe2x80x9caxe2x80x9d in formula C is in the (S) configuration and the amide linkage between AB1 and C is formed as in Example 44, step (f).
Additional embodiments of methods for forming the amide linkages of the processes of this invention are described in the Examples, and it is to be understood that each of the embodiments exemplified as described below are intended to be included within the scope of the processes of this invention.
In a further embodiment of the above process, the compound of formula AB1 is prepared by a process which comprises forming an amide linkage between a compound of the formula A: 
and a compound of the formula B1: 
wherein Lc is a carboxylic acid and Le is a carboxylic acid (C1-C6)alkyl ester, and R2-R11 are as defined above.
In an embodiment, the amide linkage between A and B1 is formed by a process comprising (a) combining A and B1 with a suitable base, e.g. DIEA, a carbodiimide, e.g., EDC.HCl, and a catalyst, e.g. HOBT, in an organic solvent, e.g. DMF, followed by (b) distillation of volatile components, (c) partition between organic solvent and dilute aqueous acid, (d) replacement by distillation of the solvent with a non-solvent, e.g. tert-butyl methyl ether, diisopropyl ether or propan-1-ol, and (e) isolation of the product AB1-e by filtration.
In another embodiment, the amide linkage between A and B1 is formed by a process comprising (a) combining A with a chlorinating agent, e.g. oxalyl chloride or preferably thionyl chloride, in a compatible solvent e.g. toluene, acetonitrile, or 1,2-dichloroethane, in the presence of a catalyst to prepare the acid chloride, i.e. A wherein Lc=xe2x80x94C(O)Cl, (b) optionally removing the excess reagent by distillation, (c) combining the acid chloride with B1 in the presence of a suitable base, e.g. DIEA, in compatible solvents, e.g. DCE, Toluene, EtOAc, acetonitrile, and mixtures thereof, followed by (d) isolation of product AB1-e as described in the preceding embodiment, or preferably by filtration of crude product from the reaction mixture, and reslurry of the crude in suitable non-solvents, preferably in mixtures of aqueous apropan-2-ol, before refiltration.
A preferred feature of the above embodiment is the use of catalysis in the preparation of the acid chloride, i.e. A wherein Lc=xe2x80x94C(O)Cl, to prevent the formation of the corresponding symmetrical carboxylic anhydride. Preferred catalysts are tertiary amides, e.g. DMF and DMAC, or pyridines, e.g. pyridine or DMAP or mixtures thereof. More preferred catalysts are tertiarybenzamides, e.g. N,N-dimethylbenzamide. Even more preferred catalysts are N-alkyl lactams, e.g. N-methylpyrrolidinone. Catalysis by iron salts and by tetraalkylureas, e.g. tetramethylurea, is known in the art.
The invention also relates to a compound of the formula AB1
wherein R3 is H, halo or (C1-C6)alkyl, R4 and R9 are each independently H or (C1-C6)alkyl; m, n, and p are all 0, R10 is phenyl optionally substituted with from one to five R13 groups and Lc is a carboxylic acid or salt thereof. In a preferred embodiment, Lc is COOH. In another preferred embodiment, Lc is a salt of the carboxylic acid, preferrably Lc is the sodium salt of the carboxylic acid, i.e., xe2x80x94COOxe2x88x92Na+, more preferably Lc is the potassium salt of the carboxylic acid, i.e., xe2x80x94COOxe2x88x92K+, and particularly preferably Lc is the potassium salt of the carboxylic acid, i.e., xe2x80x94COOxe2x88x92K+, crystallizing as a 2.5 mole hydrate. In a preferred embodiment of the compound of formula AB1, R3 is H or halo, R4 is methyl, ethyl or propyl; m, n and p are both 0, and R10 is phenyl optionally substituted with one or two R13 groups. In a more preferred embodiment thereof, R3 is H and R4 is methyl. In another more preferred embodiment thereof, R3 is H, R4 is methyl and R10 is phenyl optionally substituted with one R13 group. In a particularly preferred embodiment, R3 is H, R4 is methyl and R10 is phenyl substituted with one trifluoromethyl group. In a particularly preferred embodiment thereof, the trifluoromethyl group is in the 4xe2x80x2 position of the biphenyl group formed between R10 and the phenyl to which it is attached.
The invention also relates to a compound of the formula AB1-e, wherein R2-R11 are as defined above for the compound AB1, and Le is a carboxylic acid ester. In an embodiment, the ester is an alkyl ester, preferably a (C1-C6) alkyl ester or a substituted-alkyl variation thereon. In a preferred embodiment, Le is the ethyl carboxylic acid ester, i.e., xe2x80x94C(O)OCH2CH3. In another preferred embodiment, Le is the methyl carboxylic acid ester, i.e., xe2x80x94C(O)OCH3.
The invention also relates to process for preparing a compound of formula C 
or a stereoisomer thereof, which comprises reacting an amine of the formula HNR6R7 with a compound of the formula 
wherein Rp is H or a protecting group.
In an embodiment, the protecting group is tert-butyloxycarbonyl (xe2x80x9cBOCxe2x80x9d). In another embodiment, the process comprises combining Cxe2x80x2 with a catalyst, e.g. HOBt, and a carbodiimide in a suitable solvent, and adding the amine HNR6R7. In a preferred embodiment, the carbodiimide is N,Nxe2x80x2-dicyclohexylcarbodiimide. In another preferred embodiment, the carbodiimide is EDC. In another preferred embodiment, the suitable solvent is dichloromethane. In a preferred embodiment, the mixture of Cxe2x80x2, the amine HNR6R7, HOBt and carbodiimide is stirred for about 30 minutes to 24 hours before further processing. In an embodiment, the further processing comprises an aqueous work-up to provide the compound of formula C. In a preferred embodiment, the amine HNR6R7 is N-methylbenzylamine, i.e., R6 is methyl and R7 is benzyl. In another preferred embodiment, RP is BOC and the amine is N-methylbenzylamine, and in a more preferred embodiment thereof, the resulting compound of formula C, (tert-butyl (RS)-2-[benzyl(methyl)amino]-2-oxo-1-phenylethylcarbamate), is treated with trifluorocaetic acid and triethylsilane in dichloromethane, followed by aqueous workup to yield (RS)-N-benzyl-N-methyl-2-phenylglycinamide. In a particularly preferred embodiment, Rp is BOC and the amine is N-methylbenzylamine, and in a more preferred embodiment thereof, the resulting optically enriched compound of formula C, (tert-butyl (S)-2-[benzyl(methyl)amino]-2-oxo-1-phenylethylcarbamate), is treated with concentrated hydrochloric acid in propan-2-ol, followed by advantageous precipitation of (S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride monohydrate from mixtures of propan-2-ol and tert-butyl methyl ether, resulting in a useful increase in the degree of optical enrichment.
A salt of the phenylglycine amide may be prepared, e.g., by treating the amide, e.g., (RS)-N-benzyl-N-methyl-2-phenylglycinamide, with di(o-toluoyl)-L-tartaric acid in a suitable solvent, e.g. ethyl acetate, to provide the di(o-toluoyl)-L-tartrate) salt, e.g. (RS)-N-benzyl-N-methyl-2-phenylglycinamide. Tartrate salts of the phenylglycine amides may be broken to provide the amide, which may be purified as its hydrochloride salt.
In another embodiment, racemic compounds of the formula C may be resolved via the selective precipitation of one of the enatiomers as its salt with an optically enriched chiral acid, of which many examples are known in the art, from suitable solvents, e.g. methanol and ethanol. Such optically enriched chiral acids may be naturally occuring or synthetic. The precipitated salts may be hydrates or solvates.
In a preferred embodiment, (RS)-N-benzyl-N-methyl-2-phenylglycinamide is treated with di(o-toluoyl)-L-tartaric acid in methanol at 20xc2x0 C. The precipitated salt is filtered and washed with methanol, then dried providing (S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate with 92.7% d.e. (chiral HPLC). This material is reslurried in hot methanol, filtered, washed and dried to providing (S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate with 99% d.e. (37% overall yield).
The diastereomericly enriched salts formed as described in the previous embodiments may be broken to provide optically enriched free amines C, e.g. (S)-N-benzyl-N-methyl-2-phenylglycinamide, which may be advantageously purified by crystallization as-is or by the formation of a salt with an achiral acid in the presence of suitable solvents, e.g. precipitation of (S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride from mixtures of propan-2-ol and tert-butyl methyl ether.
In another embodiment, a racemic compound of the formula C may be resolved via the selective recrystallization of its salt with an optically enriched chiral acid, e.g. (RS)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate prepared as described above, from a suitable solvent, to provide diastereomericly enriched salts, e.g. (S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate. Breakage of these salts delivers optically enriched free amines of the formula C, which may be advantageously isolated and used as the hydrochloride salt, e.g. (S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride.
In another embodiment, where optically enriched compunds C are preferred, the unwanted enantiomer of the compound C may be recycled by racemization. In a more preferable embodiment, the racemization is applied to mother liquors from the resolutions described above by refluxing in the presence of a catalytic amount of a carbonyl compound, e.g. 2-chlorobenzaldehyde, thus allowing the isolation of second crops of diastereomerically enriched salts containing the desired enatiomer of compound C, e.g. (S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate with 92% d.e. in approximately 50% yield of the solute in the initial ethanolic mother liquors. In a still more preferred embodiment, the catalysed racemization is performed at a suitable temperature and concentration in-situ during the resoluton in a suitable solvent, prior to the isolation of the first crop of product; this xe2x80x9cdynamic resolutionxe2x80x9d allows a first crop yield of product to be significantly greater than the 50% available by traditional salt resolutions. Dynamic resoultions are known in the art, but are considered far from trivial and highly substrate dependant.
In still another embodiment of a process for preparing an opticaly enriched compound of formula C, a homochiral amino acid, e.g. (S)-L-2-phenylglycine, is converted to the corresponding N-carboxyanhydride, e.g. (S)-4-phenyl-1,3-oxazolidine-2,5-dione, using methods well known in the art, which, may then be combined an amine, e.g. N-methylbenzylamine. The resulting mixture is then subjected to an aqueous work-up, providing the optically enriched aminoamide, e.g. (S)-N-benzyl-N-methyl-2-phenylglycinamide, which may be purified as-is or as a suitable salt.
The invention also relates to a process for preparing a compound of formula 2 which comprises: (a) forming an amide linkage between a compound of the formula A and a compound of the formula B2: 
and (b) forming an amide linkage between the product of step (a) and a compound of the formula C; wherein R2, R3, R9, Lc, y and A and C are as defined above.
The invention also relates to a process for preparing a compound of formula 2 which comprises forming an amide linkage between a compound of the formula AB2
and a compound of the formula C; wherein R2, R3, R9, R10, R11 and y are as defined above.
The invention also relates to a process for preparing a compound of formula 1b, wherein X1 is S or O, which comprises: (a) forming an amide linkage between a compound of the formula AB3: 
and a compound of the formula C, wherein X1 is S or O, and (b) forming an amide linkage between the product of step (a) and a compound of the formula C, wherein the compound of formula A and the compound of formula C are as defined above.
The invention also relates to a process for preparing a compound of formula 1b, wherein X1 is S or O, which comprises: (a) forming an amide linkage between a compound of the formula B3 and a compound of the formula C; and (b) forming an amide linkage between the product of step (a) and a compound of the formula A, wherein A, B3 and C are as defined above.
It is to be understood that the methods of preparing the compounds disclosed herein, including the compounds of formulas 1, 1b and 2, their varied embodiments and synthetic precursors or intermediates are not limiting but only illustrative.
The compounds of this invention are useful as MTP/ApoB inhibitors.
The terms xe2x80x9ccompound(s) of formula 1xe2x80x9d, xe2x80x9ccompound(s) of formula 1bxe2x80x9d, xe2x80x9ccompound(s) of formula 2xe2x80x9d, etc. include a compound of formula 1 (or 1b or 2, respectively) as defined herein and all of the embodiments, preferred embodiments, more preferred embodiments, and particularly preferred embodiments of such compounds, including the compounds named or exemplified herein, each of which is a particularly preferred embodiment of the compounds defined by the formulas. Reference to xe2x80x9ca compound of the inventionxe2x80x9d is meant to encompass any of the compounds of formula 1, formula 1b or formula 2 as those terms are defined above. Accordingly, reference to xe2x80x9ca compound of the inventionxe2x80x9d in connection with any of the embodiments, preferred embodiments, more preferred embodiments or particularly preferred embodiments of the compositions, processes and methods of the invention described herein, as well as embodiments relating to salts, polymorphs, solvates, hydrates, prodrugs and isotopically-labelled derivatives of the compounds of the invention, is intended to refer to any of the compounds of formula 1 (or 1b or 2 respectively) as defined above, i.e., to any of the embodiments, preferred embodiments, more preferred embodiments or particularly preferred embodiments of the compounds, especially the compounds named or exemplified herein.
This invention also relates to the salts, polymorphs, solvates and hydrates of the compounds of the invention, as well as to the salts, polymorphs, solvates and hydrates of the synthetic precursors of each of the compounds of the invention. The invention relates to polymorphs of the compound of formula 1, wherein R1-R8 are as defined above, having an X-ray powder diffraction patterns substantially the same as shown in any of FIGS. 1, 3, 4, and 5. It is to be understood that some level of noise is inherent in the generation of a diffraction pattern, i.e., peaks in intensity are to be discriminated from background according to methods well-known in the art. In a preferred embodiment, the compound is (S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4xe2x80x2-(trifluoromethyl)[1,1xe2x80x2biphenyl]-2-carboxamido]-1H-indole-2-carboxamide and the X-ray powder diffraction pattern is substantially the same as that shown in FIG. 1. In a more preferred embodiment, the compound has an X-ray powder diffraction pattern having peaks at 2-theta values substantially the same as the 2-theta values for at least ten of the peaks of highest intensity in the X-ray powder diffraction pattern shown in FIG. 1.
In an embodiment, the compound of the invention is a polymorph of the compound of formula 1 having a differential scanning calorimetry (DSC) profile substantially the same as that shown in FIG. 2. In a preferred embodiment, the compound is (S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4xe2x80x2-(trifluoromethyl)[1,1xe2x80x2-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide. In a more preferred embodiment, the compound exhibits a heat absorption onset temperature, peak temperature and characteristic shape substantially the same as that shown in FIG. 2.
The term xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of the invention. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of carboxylic acid groups and hydrochloride salts of amino groups. Other pharmaceutically acceptable salts of amino groups are hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. The preparation of such salts is described below.
The compounds of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of the invention are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
The compounds of the invention that are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and particularly, the sodium and potassium salts. This invention also encompasses pharmaceutical compositions containing, and methods of treating proliferative disorders or abnormal cell growth through administering, prodrugs of compounds of the invention. Compounds of the invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citruiline homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
In certain combination therapies with other lipid-lowering agents, such as those described hereinbelow, e.g., HMG CoA reductase inhibitors, HMG CoA synthetase inhibitors, ACAT inhibitors, squalene synthetase inhibitors, etc., a compound of the invention may further comprise a prodrug which comprises a compound of formula 1 in a hydrolyzable linkage to another anti-cancer agent. Di-ester linkages, for example, are particularly useful for this purpose, i.e., the prodrug is in the form A1xe2x80x94C(O)Oxe2x80x94L1xe2x80x94O(O)Cxe2x80x94A2, wherein A1 and A2 are the two agents, L1 is a linker such as a methylene or other (C1-C6) alkylene group (alone or further comprising a phenyl or benzyl group). The two agents may both be a compound of the invention, or one may be another agent useful for treating, e.g., obesity, as described herein. See, e.g., U.S. Pat. No. 4,342,772xe2x80x94penicillins in di-ester linkages with xcex2-lactamase inhibitors. Accordingly, a compound of the invention having an available carboxylic acid group provides just one convenient means of producing combination prodrugs of the compound of the invention, which are encompassed by this invention. Typically, the acidic conditions of the gastrointestinal tract, or enzymes localized in the cells thereof cause the hydrolysis of the prodrug, releasing both agents.
Certain compounds of the invention have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the invention, and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of the invention, this invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. Some of the compounds of the invention may also exist as tautomers, including, e.g., keto-enol tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
Furthermore, some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any and all racemic, optically-active, polymorphic and stereoisomeric forms, or mixtures thereof, which form or forms possess properties useful in the treatment of the conditions noted hereinabove, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine efficacy for the treatment of the conditions noted herein by the standard tests described hereinafter.
The subject invention also relates to isotopically-labelled compounds of the invention which are identical to those recited in formula 1, formula 1b and formula 2 but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the invention and pharmaceutically acceptable salts of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
The following selected functional group definitions and examples thereof are employed throughout the instant specification and the appendant claims and are offered by way of illustration, and not by limitation.
The term xe2x80x9calkylxe2x80x9d means both straight and branched chain saturated hydrocarbon groups. Some examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl, pentyl and hexyl.
The term xe2x80x9ccycloalkylxe2x80x9d means both straight and branched chain saturated hydrocarbon groups comprising at least one ring or cyclic structure, and unless otherwise specified, is monocyclic. Some examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Some examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
The term xe2x80x9cbicycloalkylxe2x80x9d means both straight and branched chain saturated hydrocarbon groups, optionally containing one or more double or triple bonds, comprising at least two rings or cyclic structures, which cyclic structures may contain one or more common carbon atoms, i.e., encompasses bridged bicyclic and spiro-bicyclic groups. Bicycloalkyl groups preferably contain from 5 to 12 members, more preferably, from 6 to 10 members. Preferably, each ring of a bicycloalkyl group contains from 3 to 6 members. An example of a bicycloalkyl group is spiro[4.5]decyl. In this application, the term xe2x80x9cbridgedxe2x80x9d when referring to any bicyclic group means that the two rings share at least two common atoms; the shared atoms are known in the art as xe2x80x9cbridgeheadxe2x80x9d atoms. Spiro bicyclic groups, in contrast, are bicyclic groups whose two rings share only a single bridgehead atom. Some other examples of bicycloalkyl groups are norbornyl, norbornenyl, bicyclo[3.1.0]hexyl. Bicycloalkyl groups may be in any available conformation, e.g., cis, trans, endo, exo with respect to their linkage to other groups or with respect to their substituents.
The term xe2x80x9calkenylxe2x80x9d means both straight and branched chain unsaturated hydrocarbon groups containing at least two carbons. Some examples of alkenyl groups are ethenyl, propenyl and isobutenyl.
The term xe2x80x9calkynylxe2x80x9d means both straight and branched chain hydrocarbon groups containing at least one triple bond between two carbon atoms. Some examples of alknyl groups are ethynyl and propynyl, e.g., propyn-1-yl and propyn-2-yl and propyn-3-yl.
The term xe2x80x9calkoxyxe2x80x9d means a straight or branched chain hydrocarbon group attached through an oxygen atom. Some examples of alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, hexoxy and heptoxy.
The term xe2x80x9cacylxe2x80x9d means either a straight or branched chain hydrocarbon moiety attached through a carbonyl group. Some examples of acyl groups are acetyl, propionyl, butyryl and isobutyryl.
The terms xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d mean fluoro, chloro, bromo, and iodo groups, unless specified otherwise.
The term xe2x80x9chaloalkylxe2x80x9d, as used herein, unless otherwise indicated, means an alkyl group substituted with one or more halo groups, on one or more carbon atoms. Preferably, the haloalkyl comprises 1 to 3 halo groups, such as a hydrocarbon comprising a dichloromethyl group, or a monohalosubstituted hydrocarbon.
The term xe2x80x9cperfluoroxe2x80x9d, when used in conjunction with a specified hydrocarbon group, is meant to include a substituent wherein the individual hydrogen atoms thereof are substituted therefor with fluorine atoms, preferably, wherein all the individual hydrogen atoms thereof are substituted therefor with fluorine. Some examples of perfluoro groups are trifluoromethyl (perfluoromethyl), pentafluoroethyl (perfluoroethyl) and heptafluoropropyl (perfluoropropyl).
The term xe2x80x9calkoxycarbonylxe2x80x9d means an alkoxy group attached through a carbonyl group. Some examples of alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and butoxycarbonyl.
The term xe2x80x9calkylthioxe2x80x9d means an alkyl group attached through a sulfur atom. Some examples of alkylthio groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio and hexylthio.
The term xe2x80x9calkylaminoxe2x80x9d means an alkyl group attached through a nitrogen atom, wherein the nitrogen is unsubstituted, i.e., the group is alkyl-NHxe2x80x94. Some examples of alkylamino groups are methylamino, ethylamino, propylamino, isopropylamino, butylamino and isobutylamino.
The term xe2x80x9cdialkylaminoxe2x80x9d means an alkylamino group wherein the nitrogen atom is substituted with two independent alkyl groups Ra and Rb, i.e., xe2x80x94N(RaRb). Some examples of dialkylamino groups are dimethylamino, diethylamino, dipropylamino and di-isopropylamino as well as N-methyl-Nxe2x80x2-ethylamino, N-ethyl-Nxe2x80x2-propylamino and N-propyl-Nxe2x80x2-isopropylamino.
Some examples of acyloxy groups include acetyloxy, propionyloxy, butyryloxy, and also include such radicals which incorporate a cyclic substituent such as benzoyloxy.
The term xe2x80x9chaloalkoxyxe2x80x9d, as used herein, unless otherwise indicated, means an xe2x80x94O-haloalkyl group wherein xe2x80x9chaloalkylxe2x80x9d is as defined above. An example of a haloalkoxy group is trifluoromethoxy.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, means an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl. Aryl is most preferably phenyl. It is to be understood that a napthyl group may be bonded through any position, i.e., napth-1-yl, napth-2-yl, napth-3-yl, napth-4-yl.
The terms xe2x80x9cheterocyclylxe2x80x9d and xe2x80x9cheterocyclicxe2x80x9d, as used herein, unless otherwise indicated, mean non-aromatic (saturated or unsaturated) monocyclic and multicyclic groups containing one or more heteroatoms each selected from O, S and N, wherein each ring of a heterocyclic group has from 3 to 8 atoms. Preferably, heterocyclic groups of this invention are monocyclic or bicyclic.
Monocyclic heterocyclic groups include rings having only 4 atoms; preferably, monocyclic heterocyclic groups contain from 4 to 8 members, and more preferably, from 4 to 6 members, and most preferably, 5 or 6 members. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine), an example of a 5-membered heterocyclic group is imidazolidinyl, and an example of a 6-membered heterocyclic group is piperidinyl. Other examples of monocyclic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxoianyl, 1,4-dithianyl, pyrazolinyl, pyrazolidinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl and imidazolinyl. Other examples of monocyclic heterocyclic groups include azacycloheptane and azacyclooctane. Preferred monocyclic heterocyclic groups are azetidinyl, pyrrolidinyl, piperidinyl and morpholino. Monocyclic heterocyclic groups may be referred to herein as xe2x80x9cheteromonocyclyl.xe2x80x9d
Bicyclic heterocyclic groups may be referred to herein as xe2x80x9cheterobicyclicxe2x80x9d or xe2x80x9cheterobicyclylxe2x80x9d, both of which as used herein mean heterocyclic groups containing two rings, and encompass fused-ring bicyclic, bridged bicyclic and spiro-bicyclic groups. Heterobicyclic groups preferably contain from 5 to 12 members, more preferably, from 6 to 10 members. Preferably, each ring of a heterobicyclic group contains from 3 to 6 members. An example of a heterobicyclic group is 1,4-dioxaspiro[4.5]decyl. Some other examples of heterobicyclic groups include azabicyclohexyl, e.g., 3-azabicyclo[3.1.0]hexyl, azabicycloheptyl, e.g., 2-azabicyclo[2.2.1]heptyl and azabicyclooctyl.
The term xe2x80x9cheteroarylxe2x80x9d as used herein means aromatic heterocyclic groups comprising from 5 to 12 atoms and containing one or more heteroatoms each selected from O, S and N, wherein each ring of the heteroaryl group contains from 3 to 8 atoms. Heteroaryl groups of this invention unless otherwise indicated may contain one ring or more than one ring, i.e., they may be monocyclic or multicyclic, for example bicyclic, so long as at least one ring in a multicyclic group is aromatic. Preferably, heteroaryl groups of this invention are monocyclic or bicyclic. Preferably, each ring of a heteroaryl group contains one or two heteroatoms. Monocyclic heteroaryl groups preferably contain from 5 to 8 members, more preferably, 5 or 6 members. Preferably, the monocyclic heteroaryl groups containing two heteratoms contain two nitrogen atoms, a nitrogen atom and an oxygen atom, or a nitrogen atom and a sulfur atom. Some examples of monocyclic heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thiophenyl (referred to hereinafter as xe2x80x9cthienylxe2x80x9d), isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl and furazanyl (i.e., 2,5-diaza-furanyl). Preferred among the monocyclic heteroaryl groups are thienyl, furyl and pyridinyl. More preferred monocyclic heteroaryl groups are thien-2-yl, fur-2-yl, pyridin-2-yl, pyridin-3-yl, i.e., attached through the 2- or 3-carbon, respectively. A particularly preferred monocyclic heteroaryl group is pyridyl. The term xe2x80x9cpyridylxe2x80x9d as used in this application, unless otherwise specified, means 2-pyridyl, 3-pyridyl or 4-pyridyl, i.e., pyridyl attached through any available carbon atom.
Multicyclic heteroaryl groups are preferably bicyclic; bicyclic heteroaryl groups preferably contain 9 or 10 members. Some examples of heteroaryl groups are quinolinyl, isoquinolinyl, indolyl, 3H-indolyl, indolinyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, pteridinyl, benzothiadiazine, benzothiazinyl, 2H-1-benzopyranyl, chromanyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.
The foregoing heterocyclic and heteroaryl groups may be C-attached or N-attached where such is possible. For instance, pyrrolyl may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). The heterocyclic groups of this invention also include ring systems substituted with one or more oxo moieties.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, unless otherwise indicated, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
The invention further relates to a pharmaceutical composition comprising a compound of formula 1 and a pharmaceutically acceptable carrier. The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefor, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired. Aqueous compositions of the present invention may comprise other pharmaceutically acceptable solutes including additives and other therapeutic agents, as appropriate. Suitable additives are those well known in the art including, but not limited to, antioxidants, antibacterials, surfactants, chelating agents, sugars, and preservatives. Aqueous compositions of the invention can be administered by injection, which can be intramuscular, intravenous or preferably subcutaneous. A dose of from about 0.5 xcexcg/Kg/day to about 10 xcexcg/Kg/day, preferably from about 1 xcexcg/Kg/day to 5 xcexcg/Kg/day, can be used.
Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. For examples, see Remington: The Practice of Pharmacy, Lippincoft Williams and Wilkins, Baltimore Md., 20th ed. 2000.
The compounds of the invention can be administered alone but will generally be administered in an admixture with suitable pharmaceutical excipient(s), diluent(s) or carrier known in the art and selected with regard to the intended route of administration and standard pharmaceutical practice. If appropriate xe2x80x9cauxiliaryxe2x80x9d agents may also be added, which includes preservatives, anti-oxidants, flavors or colorants. The compound of the invention may be formulated to provide immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release dependent on the specific route of administration and the specificity of release profile, commensurate with therapeutic needs.
The compounds of the invention can be administered, for example but not limited to, the following route: oral (including buccal, sublingual, etc.) in the forms that are well known in the art (ref.) for veterinary and pharmaceutical applications. xe2x80x9cOralxe2x80x9d in this instance refers to oral mode of administration wherein the forms are explicitly provided to the animals for oral consumption i.e., on-diet, in-drinking fluid, placed directly into the oral cavity, or offered for free-choice consumption. In this invention, the term xe2x80x9canimalxe2x80x9d includes a warm-blooded animal of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds, preferably companion animals and livestock animals, and humans. Some examples of companion animals are canines, e.g., dogs, felines, e.g., cats and horses; some examples of livestock animals are pigs, cows, sheep and the like. Preferably, the animal is a mammal. More preferably, the mammal is a companion animal or a livestock animal.
Typical oral solid forms may include tablets, powders, multi-particulate preparations (granules), capsules, chews, lozenges, films, patches, etc. Typical oral liquid (including semi-solid and colloidal) forms may include solutions, elixirs, gels, sprays, liquid-filled chews, etc. Other oral forms wherein the active agent is suspended in a liquid or semi-solid carrier phase, for example suspensions, may also be used.
The preferred oral solid, liquid and suspension forms for a compound of the invention are those that impart flexibility in dosing to the animals, wherein the method of administration is facile and the dose can be accurately and flexibly controlled in keeping with the need of the therapy. Examples of such forms include tablet preparations, solutions (and similar forms thereof as described herein) and suspensions. In these examples, the dose can be easily controlled for oral administration. Particularly for solutions and suspensions, the utility of appropriate metering systems (i.e., calibrated syringes etc.) provides high flexibility in controlling the dose to facilitate administration to animal species of different sizes or to different animal species or breeds, with varying dose requirements. Additionally, the utility of flavoring/palatability agents and/or texture enhancers in the said forms can promote animal acceptance and compliance, which can be particularly advantageous when dosing chronically to animals.
The compounds of the invention may also be administered via the parenteral routes. The term parenteral in this context refers to all routes of drug administration that is not via the oral cavity. Preferably for the compounds of the innovation, parenteral routes may include topical and transdermal, rectal, vaginal, nasal, inhalation and injectables (i.e., administration modes that require penetration of the skin barrier via needle and needle-less methods, including implants and reservoirs). Formulations for these routes of administration may be prepared in a conventional manner in accordance with standard pharmaceutical and veterinary practices, illustrative examples of which are described herein.
Particularly preferred compositions of the compounds of the invention comprise oral solid forms, examples of which are provided below, are preferably tablets, powders or granules which typically contain just the active agent(s) or preferably in combination with adjuvants/excipients.
In an embodiment of the invention, the pharmaceutical composition comprises a compound the invention, herein referred to also as xe2x80x9cthe activexe2x80x9d in an amount typically less than 50% (by weight) of the formulation and preferably less than 10%, more preferably, about 2.5% by weight, and a pharmaceutically acceptable carrier. In a preferred embodiment, the predominant portion of the formulation comprises fillers, diluents, disintegrants, lubricants and optionally, flavors. The composition of these excipients is well known in the art. In an embodiment of the invention, the preferred fillers/diluents comprise admixtures of two or more of the following components: avicel, mannitol, lactose (all types), starch, and di-calcium phosphate. In preferred embodiments of the compositions, the filler/diluent admixtures typically comprises less than 98% (by weight) of the formulation and preferably less than 95%, for example 93.5%. In a preferred embodiment, disintegrants include Ac-di-sol, Explotab(trademark), starch and sodium lauryl sulphate (SLS)xe2x80x94also known as wetting agent. In a more preferred embodiment, the amount of filler/diluent admixture usually comprises less than 10% (by weight) of the composition and preferably less than 5%; in a particularly preferred embodiment, the amount is about 3%. In a particularly preferred embodiment, the lubricant is magnesium stearate. In preferred embodiments thereof, the magnesium stearate is present in an amount less than about 5% of the formulation and preferably less than about 3%, more preferably, about 1%. Preferably, lubricants comprise less than 60% of the formulation, preferably less than 40%, and most preferably, from about 10% to about 20%. Particularly preferred embodiments of tablet formulations for the compounds of the invention are shown in Table 10.
The compositions of the invention include tablets. In a preferred embodiment, tablets are manufactured by a process selected from direct compression or a wet, dry or melt granulation, melt congealing process and extrusion. In another embodiment, tablet cores of the compositions of the invention may be mono or multi-layer(s) and can be coated with appropriate overcoats known in the art.
Oral liquid forms of the compounds of the invention are preferably solutions, wherein the active compound is fully dissolved. In an embodiment, the solution comprises the active and a pharmaceutically precedented solvents suitable for oral administration. In a preferred embodiment, the solvent is one in which the compounds of the invention show good solubility. In a more preferred embodiment, the solution comprises a solvent selected from polyethylene glycol, polypropylene glycol, edible oils and glyceryl- and glyceride-based systems. In more preferred embodiments, glyceryl- and glyceride-based systems comprise agents selected from Captex 355 EP, Crodamol GTC/C, or Labrafac CC, triacetin, Capmul CMC, Migyols (812, 829, 840), Labrafil M1944CS, Peceol and Maisine 35-1. The exact composition of these agents and commercial sources are shown in Table 11. These solvents usually make up the predominant portion of the formulation i.e., greater than 50% (by weight) and preferably greater than 80%, for example 95% and more preferably greater than 99%. In preferred embodiments, the solution further comprises an adjuvant or additives. In a preferred embodiment thereof, the additive or adjuvant is a taste-mask agent, palatability agent, flavoring agent, antioxidant, stabilizer, texture modifier, viscosity modifier, or a solubilizer.
A further embodiment is a process for preparing preferred oral liquid form of the compounds of the invention (see the Pharmaceutical Compositions section), wherein the individually preferred components are combined optionally with mechanical or ultrasonic agitation in a preferred temperature range, in such a fashion that is advantageous to the rate of dissolution.
The compounds of the instant invention inhibit or decrease Apo B secretion, likely by the inhibition of MTP, although it may be possible that other mechanisms are involved. The compounds are useful in treating any of the disease states or conditions in which Apo B, serum cholesterol, and/or triglyceride levels are elevated. Thus, the compositions of this invention are useful for the treatment of conditions including atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia and diabetes. Accordingly, this invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention, including the stereoisomers, pharmaceutically acceptable salts and solvates thereof, in combination with a pharmaceutically acceptable carrier or diluent.
The instant invention also relates to a method for inhibiting or decreasing Apo B secretion in an animal in need thereof which comprises the administration of an Apo B secretion inhibiting or decreasing amount of a compound of the invention or a stereoisomer, pharmaceutically acceptable salt or solvate thereof. The invention further provides a method of treating a condition selected from atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, and diabetes which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of formula 1 (or 1b or 2) or a stereoisomer, pharmaceutically acceptable salt or solvate thereof. A preferred subgroup of the conditions described hereinabove is atherosclerosis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, and diabetes.
In one aspect, the present invention concerns the treatment of diabetes, including impaired glucose tolerance, insulin resistance, insulin dependent diabetes mellitus (Type I) and non-insulin dependent diabetes mellitus (NIDDM or Type II). Also included in the treatment of diabetes are the diabetic complications, such as neuropathy, nephropathy, retinopathy or cataracts.
Diabetes can be treated by administering to an animal having diabetes (Type I or Type II), insulin resistance, impaired glucose tolerance, or any of the diabetic complications such as neuropathy, nephropathy, retinopathy or cataracts, a therapeutically effective amount of a compound of the present invention. It is also contemplated that diabetes be treated by administering a compound of the invention along with other agents that can be used to treat diabetes. Preferably, the diabetes is Type II diabetes. More preferably, the animal is feline; even more preferably, the feline is a cat.
Accordingly, this invention further relates to a method of treating Type II diabetes in an animal in need of such treatment, which comprises administering to the animal a therapeutically effective amount of a compound of formula 1 or a stereoisomer, pharmaceutically acceptable salt or solvate thereof.
The invention also provides a method of treating Type II diabetes in an animal in need of such treatment, which comprises administering to the animal a therapeutically effective amount of a compound of formula 1 or a stereoisomer, pharmaceutically acceptable salt or solvate thereof, in combination with one or more additional agents capable of treating Type II diabetes in the animal.
Representative agents that can be used to treat diabetes include insulin and insulin analogs (e.g. LysPro insulin); GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH2; sulfonylureas and analogs: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide(copyright), glimepiride, repaglinide, meglitinide; biguamides: metformin, phenformin, buformin; xcex12-antagonists and imidazolines: midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulin secretagogues: linogliride, A-4166; glitazones: ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone, BRL49653; fatty acid oxidation inhibitors: clomoxir, etomoxir; xcex1-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945; xcex2-agonists: BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243; phosphodiesterase inhibitors: L-386,398; lipid-lowering agents: benfluorex; antiobesity agents: fenfluramine and orlistat; vanadate and vanadium complexes (e.g. Naglivan(copyright)) and peroxovanadium complexes; amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors; somatostatin analogs; antilipolytic agents: nicotinic acid, acipimox, WAG 994; and glycogen phosphorylase inhibitors, such as those disclosed in WO 96/39385 and WO 96/39384. Also contemplated in combination with compounds of the invention are pramlintide acetate (Symlin(trademark)) and nateglinide. Any combination of agents can be administered as described above.
The invention also relates to a method of treating obesity in a mammal which comprises administering to an animal in need of such treatment an effective amount of an intestinal-MTP-selective compound, wherein the ED25 of the compound for the inhibition of intestinal fat absorption is at least 5-fold lower than the ED25 of the compound for the lowering of serum triglycerides. In an embodiment, the ED25 for the inhibition of intestinal fat absorption is at least 10-fold lower than the ED25 of the compound for the lowering of serum triglycerides. In another embodiment, the compound exhibits an ED25 for the inhibition of intestinal fat absorption which is at least 50-fold lower than the ED25 of the compound for the lowering of serum triglycerides.
In another embodiment, the intestinal-MTP-selective compound is a compound of formula 1, 1b or 2, or an embodiment, preferred embodiment, more preferred embodiment, or particularly preferred embodiment of a compound of formula 1, 1b or 2.
In this invention, the term xe2x80x9cselectivityxe2x80x9d refers to a greater effect of a compound in a first assay, compared to the effect of the same compound in a second assay. In the above embodiment of the invention, the first assay is for the ability of the compound to inhibit intestinal fat absorption and the second assay is for the ability of the compound to lower serum triglycerides. In a preferred embodiment, the ability of the compound to inhibit intestinal fat absorption is measured by the ED25 of the compound in an intestinal fat absorption assay, such that a greater effect of the compound results in the observation of a lower absolute (numerical) value for the ED25. In another preferred embodiment, the ability of the compound to lower serum triglycerides is measured by the ED25 of the compound in a serum triglyceride assay. Again, a greater effect of a compound in the serum triglyceride lowering assay results in the observation of a lower absolute (numerical) value for the ED25. An illustrative example of each assay is provided hereinbelow, but it is to be understood that any assay capable of measuring the effectiveness of a compound in inhibiting intestinal fat absorption, or capable of measuring the effectiveness of a compound in lowering serum triglycerides, is encompassed by the present invention.
In a particularly preferred embodiment, the intestinal-MTP-selective compound is a compound of formula 1b, wherein X1 is N(R4) or O, X2 is C(H); m, n and p are all 0; R3 is H or Cl; R4 is CH3; R5 and R9 are both H; R10 is phenyl (with carbons numbered 1xe2x80x2-6xe2x80x2) substituted at the 4xe2x80x2-position with CF3, or R10 is (C1-C6)alkoxy; R6 is H or methyl and R7 is (C1-C6)alkyl or benzyl, wherein the benzyl is optionally substituted with (C1-C6)alkyl or (C1-C6)alkoxy.
The compounds of this invention may be used in conjunction with other pharmaceutical agents, including other lipid lowering agents. Such agents include, for example, cholesterol biosynthesis inhibitors and cholesterol absorption inhibitors, especially HMG-CoA reductase inhibitors and HMG-CoA synthase inhibitors; HMG-CoA reductase gene expression inhibitors; CETP inhibitors; bile acid sequestrants; fibrates; cholesterol absorption inhibitors; ACAT inhibitors, squalene synthetase inhibitors, ion-exchange resins, anti-oxidants and niacin. In combination therapy treatment, the compounds of the instant invention and the other drug therapies may be administered to animals (e.g. humans) by conventional methods.
This invention provides a method of treating atherosclerosis; pancreatitis secondary to hypertriglyceridemia; hyperglycemia (1) by causing a reduced absorption of dietary fat through MTP inhibition, (2) by lowering triglycerides through MTP inhibition or (3) by decreasing the absorption of free fatty acids through MTP inhibition; in an animal in need of treatment thereof, which comprises administering to the animal a therapeutically effective amount of the compound of formula 1, 1b or 2.
The invention also provides a pharmaceutical composition comprising: a) a therapeutically effective amount of a first compound, wherein said first compound is a compound of claim 1 or a stereoisomer, pharmaceutically acceptable salt or hydrate thereof; b) a therapeutically effective amount of a second compound, wherein said second compound is selected from a cholesterol absorption inhibitor, a CETP inhibitor, an HMG-CoA reductase inhibitor, an HMG-COA synthase inhibitor, an inhibitor of HMG-CoA reductase gene expression, niacin, an antioxidant, an ACAT inhibitor or a squalene synthetase inhibitor; and c) a pharmaceutically acceptable carrier or diluent. In a preferred embodiment of the invention, the said second compound is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin. In a more preferred embodiment of the invention, said second compound is atorvastatin.
Specific cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors are described in detail hereinbelow. Additional cholesterol absorption inhibitors are known to those skilled in the art and are described, for example, in PCT WO 94/00480.
Any HMG-CoA reductase inhibitor may be employed as the second compound in the combination therapy aspect of the instant invention. The term HMG-CoA reductase inhibitor refers to a compound which inhibits the biotransformation of hydroxymethylglutaryl-coenzyme A to mevalonic acid as catalyzed by the enzyme HMG-CoA reductase. Such inhibition may be determined readily by one of skill in the art according to standard assays (e.g., Methods of Enzymology, 1981; 71: 455-509 and the references cited therein). A variety of these compounds are described and referenced hereinbelow. U.S. Pat. No. 4,231,938 (the disclosure of which is hereby incorporated by reference) discloses certain compounds isolated after cultivation of a microorganism belonging to the genus Aspergillus, such as lovastatin. Also, U.S. Pat. No. 4,444,784 (the disclosure of which is hereby incorporated by reference) discloses synthetic derivatives of the aforementioned compounds, such as simvastatin. Additionally, U.S. Pat. No. 4,739,073 (the disclosure of which is hereby incorporated by reference) discloses certain substituted indoles, such as fluvastatin. Further, U.S. Pat. No. 4,346,227 (the disclosure of which is hereby incorporated by reference) discloses ML-236B derivatives, such as pravastatin. In addition, EP 491,226 teaches certain pyridyidihydroxyheptenoic acids, such as rivastatin. Also, U.S. Pat. No. 4,647,576 (the disclosure of which is hereby incorporated by reference) discloses certain 6-[2-(substituted-pyrrol-1-yl)alkyl]-pyran-2ones such as atorvastatin. Other HMG-CoA reductase inhibitors will be known to those skilled in the art.
Any HMG-CoA synthase inhibitor may be used as the second compound in the combination therapy aspect of this invention. The term HMG-CoA synthase inhibitor refers to a compound which inhibits the biosynthesis of hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase. Such inhibition may be determined readily by one of skill in the art ac cording to standard assays (e.g., Methods of Enzymology, 1975; 35: 155-160 and Methods of Enzymology, 1985; 110: 19-26 and the references cited therein). A variety of these compounds are described and referenced hereinbelow. U.S. Pat. No. 5,120,729 (the disclosure of which is hereby incorporated by reference) discloses certain beta-lactam derivatives. U.S. Pat. No. 5,064,856 (the disclosure of which is hereby incorporated by reference) discloses certain spiro-lactone derivatives prepared by culturing the microorganism MF5253. U.S. Pat. No. 4,847,271 (the disclosure of which is hereby incorporated by reference) discloses certain oxetane compounds such as 11-(3hydroxymethyl-4-oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undecadienoic acid derivatives. Other HMG-CoA synthase inhibitors will be known to those skilled in the art.
Any compound that decreases HMG-CoA reductase gene expression may be used as the second compound in the combination therapy aspect of this invention. These agents may be HMG-COA reductase transcription inhibitors that block the transcription of DNA or translation inhibitors that prevent translation of mRNA coding for HMG-CoA reductase into protein.
Such inhibitors may either affect transcription or translation directly, or may be biotransformed into compounds that have the aforementioned attributes by one or more enzymes in the cholesterol biosynthetic cascade or may lead to the accumulation of an isoprene metabolite that has the aforementioned activities. Such regulation is readily determined by those skilled in the art according to standard assays (Methods of Enzymology, 1985; 110: 9-19). Several such compounds are described and referenced below however other inhibitors of HMG-CoA reductase gene expression will be known to those skilled in the art U.S. Pat. No. 5,041,432 (the disclosure of which is incorporated herein by reference) discloses certain 15-substituted lanosterol derivatives. Other oxygenated sterois that suppress the biosynthesis of HMG-CoA reductase are discussed by E. I. Mercer (Prog. Up. Res., 1993; 32: 357-416).
Any compound having activity as a CETP inhibitor can serve as the second compound in the combination therapy aspect of the instant invention. The term CETP inhibitor refers to compounds which inhibit the cholesteryl ester transfer protein (CETP) mediated transport of various cholesteryl esters and triglycerides from high density lipoprotein (HDL) to low density lipoprotein (LDL) and very low density lipoprotein (VLDL). A variety of these compounds are described and referenced hereinbelow however other CETP inhibitors will be known to those skilled in the art U.S. Pat. No. 5,512,548 (the disclosure of which is incorporated herein by reference) discloses certain polypeptide derivatives having activity as CETP inhibitors, while certain CETP-inhibitory rosenonolactone derivatives and phosphate-containing analogs of cholesteryl ester are disclosed in J. Antibiot., 1996; 49(8): 815-816, and Bioorg. Med. Chem. Left; 1996; 6: 1951-1954, respectively.
Any ACAT inhibitor can serve as the second compound in the combination therapy aspect of this invention. The term ACAT inhibitor refers to compounds which inhibit the intracellular esterification of dietary cholesterol by the enzyme acyl CoA:cholesterol acyltransferase. Such inhibition may be determined readily by one of skill in the art according to standard assays, such as the method of Heider et al. described in Journal of Lipid Research., 1983; 24: 1127. A variety of these compounds are described and referenced hereinbelow however other ACAT inhibitors will be known to those skilled in the art.
U.S. Pat. No. 5,510,379 (the disclosure of which is incorporated by reference) discloses certain carboxysulfonates, while WO 96/26948 and WO 96/10559 both disclose urea derivatives having ACAT inhibitory activity.
Any compound having activity as a squalene synthetase inhibitor can serve as the second compound in the combination therapy aspect of the instant invention. The term squalene synthetase inhibitor refers to compounds that inhibit the condensation of two molecules of farnesylpyrophosphate to form squalene, a reaction that is catalyzed by the enzyme squalene synthetase. Such inhibition is readily determined by those skilled in the art according to standard methodology (Methods of Enzymology 1969; 15: 393-454 and Methods of Enzymology 1985; 110: 359-373 and references cited therein). A summary of squalene synthetase inhibitors has been complied (Curr. Op. Ther. Patents (1993) 861-4). European patent application publication No. 0 567 026 A1 discloses certain 4,1-benzoxazepine derivatives as squalene synthetase inhibitors and their use in the treatment of hypercholesterolemia and as fungicides. European patent application publication No. 0 645 378 A1 discloses certain seven- or eight-membered heterocycles as squalene synthetase inhibitors and their use in the treatment and prevention of hypercholesterolemia and fungal infections. European patent application publication No. 0 645 377 A1 discloses certain benzoxazepine derivatives as squalene synthetase inhibitors useful for the treatment of hypercholesterolemia or coronary sclerosis. European patent application publication No. 0 611 749 A1 discloses certain substituted amino acid derivatives useful for the treatment of arteriosclerosis. European patent application publication No. 0 705 607 A2 discloses certain condensed seven- or eight-membered heterocyclic compounds useful as antihypertriglyceridemic agents. PCT publication WO96/09827 discloses certain combinations of cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors including benzoxazepine derivatives and benzothiazepine derivatives. European patent application publication No. 0 071 725 A1 discloses a process for preparing certain optically-active compounds, including benzoxazepine derivatives, having plasma cholesterol and triglyceride lowering activities.
The present invention also provides a method of treating obesity in an animal, which comprises administering to the obese animal a compound of this invention in combination with another anti-obesity agent.
The other anti-obesity agents is preferably selected from the group consisting of a xcex23-adrenergic receptor agonist, a cholecystokinin-A (CCK-A) agonist, a monoamine reuptake inhibitor (such as sibutramine), a sympathomimetic agent, a serotoninergic agent (such as fenfluramine or dexfenfluramine), a dopamine agonist (such as bromocriptine), a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone receptor analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor (such as orlistat), a bombesin agonist, a neuropeptide-Y antagonist such as NPY-1 or NPY-5, a thyromimetic agent, dehydroepiandrosterone or an analog thereof, a glucocorticoid receptor agonist or antagonist, an orexin receptor antagonist, a urocortin binding protein antagonist, a glucagon-like peptide-1 receptor agonist, and a ciliary neurotrophic factor such as Axokine, or a human agouti-related protein (AGRP) antagonist. Other anti-obesity agents are also known, or will be apparent in light of this disclosure, to one of ordinary skill in the art.
Especially preferred anti-obesity agents comprise those compounds selected from the group consisting of sibutramine, fenfluramine, dexfenfluramine, bromocriptine, phentermine, ephedrine, leptin, phenylpropanolamine pseudoephedrine, {4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxethylamino)ethoxy]phenyl}acetic acid, {4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenyl}benzoic acid, {4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenyl}propionic acid, and {4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenoxy}acetic acid.
In preferred embodiments, the additional anti-obesity agent is another MTP/apoB inhibitor selected from the group consisting of (i) BMS-197636, also known as 9-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-propyl-9H-fluorene-9-carboxamide; (ii) BMS-200150, also known as 2-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2,3-dihydro-1H-isoindol-1-one; and (iii) BMS 201038, also known as 9-[4-(4-[2-(4-trifluoromethylphenyl)benzoylamino]piperidin-1-yl)butyl]-N-2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide; and the pharmaceutically acceptable salts of (i), (ii) and (iii). In another embodiment, the anti-obesity agent is selected from the agents disclosed in European patent application publication Nos. 0 584 446 A2 and 0 643 057 A1, the latter of which discloses certain compounds of the formulas 
which have utility as inhibitors of MTP, wherein the substituents listed in formula Ob1 are as defined in EP 0 643 057 A1. In another embodiment, the anti-obesity agent is selected from the agents disclosed in European patent application publication Nos. 1 099 439 A2, which discloses certain compounds of the formula 
wherein L in formula Ob2 is as defined as in EP 1 099 439 A2.
Preferred compounds of those disclosed in 1 099 439 A2 are compounds selected from the group consisting of 4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid-(2-butyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide and 4xe2x80x2-trifluoromethyl-biphenyl-2-carboxylic acid-(2-(2-acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide.
Methods for preparing the above agents are publicly available; for example, phentermine may be prepared as described in U.S. Pat. No. 2,408,345; sibutramine may be prepared as in U.S. Pat. No. 4,929,629; orlistat may be prepared as in U.S. Pat. No. 4,598,089; fenfluramine and dexfenfluramine may be prepared as described in U.S. Pat. No. 3,198,834; bromocriptine may be prepared as described in U.S. Pat. Nos. 3,752,814 and 3,752,888; and the substituted amino pyridines listed above may be prepared as described in PCT International Publication No. WO 96/35671; the disclosure of each of these publications is herein incorporated by reference.
It will be appreciated by those skilled in the art that certain compounds of the instant invention may contain an asymmetrically-substituted carbon atom and accordingly may exist in, and/or be isolated in, optically-active and racemic forms. Furthermore, some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any and all racemic, optically-active, polymorphic and stereoisomeric forms, or mixtures thereof, which form or forms possess properties useful in the treatment of the conditions noted hereinabove, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine efficacy for the treatment of the conditions noted herein by the standard tests described hereinafter.
The present invention may be understood more fully by reference to the detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention. The term xe2x80x9ccompound of formula 1xe2x80x9d, xe2x80x9ccompound of formula 2,xe2x80x9d as used herein, e.g., xe2x80x9ca pharmaceutical composition comprising a compound of formula 1 . . . xe2x80x9d encompasses in addition to their generic description of the compound, all of the embodiments, preferred embodiments, more preferred embodiments and particularly preferred embodiments of the compounds, as well as each of the Examples described below.